Editors' ChoiceImmunology

A Kiss That’s Just a Kiss

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Science Translational Medicine  28 Mar 2012:
Vol. 4, Issue 127, pp. 127ec52
DOI: 10.1126/scitranslmed.3004035

The adage “out with the old, in with the new” rings true in the minds of young people—but not in their immune systems, according to new work. In mice, research suggests that existing immune memory associated with bacteria, parasites, or viruses is diminished with the appearance of a new immune challenge—be it an infectious organism or a vaccine. Therefore, new infections or vaccines might cause gaps in immune surveillance that would allow latent viruses to be reactivated or that would result in a failure to respond to a repeat offender. Now, Odumade and colleagues investigate whether new infections will induce fading of preexisting immune memory to prior infections in human patients.

The authors studied young adults who were newly infected with Epstein-Barr virus (EBV). Called the “kissing disease” because of frequent oral transmission in teenagers and young adults, mononucleosis is caused by EBV, which infects 95% of the world’s population. In mouse models, EBV infection causes a huge expansion of CD8+ T cells with a strong interferon expression—a signature that is associated with attrition of immune memory. In the young patients, Odumade et al. examined how EBV infection affected populations of memory T cells that were specific for one of two other viruses—influenza A and cytomegalovirus (CMV).

Sixty-six university freshmen who contracted EBV during their first year of college were followed prospectively for 4 years. Of these 66 subjects, the authors examined in detail T cell populations in 16 students who had preexisting immune memory (measured 2 months before EBV infection) to CMV or influenza. Before, during acute EBV infection, and five months after EBV infection, the authors assessed various T cell responses, such as the percentage of total CD8+ T cells that was specific for each virus, markers for T cell activation status (granzyme B, CD38, and HLA-DR expression), and various memory T cell phenotypes. The data revealed that after EBV infection, naive T cells were not activated, effector T cells synthesized virus-thwarting cytokines, and central memory T cells self-renewed and were thought to maintain protection against their cognate viruses. To distinguish among activated memory T cells that were specific for EBV versus the other viruses, the authors made use of EBV-, CMV-, and influenza-specific tetramers—mimics of immune proteins that are normally expressed by virally infected tissues that present viral-specific peptides. The tetramers were used to mark viral-specific T cells that expressed receptors against a particular virus-peptide tetramer, and these experiments showed that EBV-specific T cells were activated after infection and expanded in numbers. Although tetramer-positive memory T cells specific for influenza A and CMV did not expand, they were indeed activated by cytokines released from the EBV-specific T cells, a phenomenon known as the bystander effect.

Although this study had a small patient population, the results are promising because they suggest that in young adults, the immune system maintains the ability to mount a robust response to a new EBV challenge without losing its prior memories. Further study is needed in larger cohorts of young patients and in older individuals to determine whether the memory-preservation phenomenon holds during aging, when a decrease occurs in the T cell repertoire in general. Also, similar trials with interferon-stimulating vaccines and adjuvants are needed to determine the effects of such immune challenges on memory T cell populations. Hopefully, all immune-provoking agents will induce, in patients of all ages, memory T cell responses that recall Old Faithful rather than “out with the old.”

O. A. Odumade et al., Primary Epstein-Barr virus infection does not erode preexisting CD8+ T cell memory in humans. J. Exp. Med. 209, 471–478 (2012). [Abstract]

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